Idiopathic calcium oxalate nephrolithiasis results from a combination of genetic and environmental factors. Genetic studies have revealed that the sisease is polygenic with two or more genetic loci contributing to the observed pattern of inheritnce. Increased urinary excretions of calcium, oxalate and citrate are three factors that contribute to stone formation and appear to be influenced y both dietary and genetic factors. It has been firmly established that hypercalciuria is an inherited trait but the pattern of inheritance has not been completely resolved. Preliminary studies have suggested that lyperoxaluria and hypocitraturia are also inherited traits. The inheritance patterns observed in calcium oxalate stone disease and in the excretions of calcium, oxalate and citrate, togeter with the distribution of their excretions in a normal population, suggest that each of these excretions is influenced by the existence of tow co-dominant alleles regulationg their excretion. Such alleles would result tin three excretory classes for each analyte. The primary focus of this proposal is to test the hypothesis that three excretory classes exist for each nanlyte and that this classification depends on inherited traits. This hypothesis will bbe tested in a large group of normal individuals by suppressing dietary influences through the use of oxalate-free formula diets as the only source of nutrition. From 24 hr urine collections participants will be classifies according to their urinary excretions of calcium, oxalate and citrate. Using this classification scheme the distribution of excretions in a calcium oxalate stone forming population and in their first degree relatives will be compared with that in the normal population to determine relative risks of stone disease associated with the various excretory levels. The pattern of inheritance will also be examined in families to confirm that it occurs in Mendelian fashion. Tests to discriminate between renal and absorptive hypercalciuria will be applied to hypercalciuric individuals in the study population and in families to conform that they are separate entities with different modes of inheritance. The research in this proposal should result in the development of better diagnostic tests to classify calcium oxalate stone formers and will aid in the identification of the genes involved in regulating calcium, oxalate and citrate excretion. Identification of these genes and an understanding of their function should ultimately lead to precise DNA tests for genotyping individuals and to the development of new therapeutic approaches for modifying excretions that promote stone formation.